THE ANTITUMOR-ACTIVITY OF DOXORUBICIN AGAINST DRUG-RESISTANT MURINE CARCINOMA IS ENHANCED BY ORAL-ADMINISTRATION OF A SYNTHETIC STAUROSPORINE ANALOG, CGP-41251

We evaluated the therapeutic efficacy against murine drug-sensitive an d drug-resistant tumor of a combination chemotherapy regimen comprisin g intravenous administration of doxorubicin (DXR) plus oral administra tion of the staurosporine analogue CGP 41251 (benzoylstaurosporine), a highly specific inhibitor of protein kinase C (PKC). In vitro studies indicated that the simultaneous presence of noncytotoxic concentratio ns of CGP 41251 with DXR decreased the median inhibitory concentration (IC50) about 3-fold in the drug-sensitive parental murine cell lines, CT-26P and UV2237. Similar treatment of drug-resistant variants of th ese tumor cell lines reversed their multiple drug resistant (MDR) phen otype (about a 5-fold increase in their sensitivity to DXR) and increa sed the cellular accumulation of DXR. Combination therapy in vivo with DXR and CGP 41251 significantly inhibited the SC growth of the drug-r esistant CT-26R500 cell line. This effect was confirmed by the ability of this combination therapy to reduce the number of lung metastases p roduced by IV injection of either the drug-sensitive parental line CT- 26P or the drug-resistant subline, CT-26R500. PKC activity was reduced in tumors derived from mice treated with either DXR or CGP 41251, but not from those derived from mice treated with the combination. These results reflect one of the infrequent examples of being able to modula te the sensitivity of in vivo-grown tumors to the antitumor effects of an MDR-related drug and suggest a basis for evaluation of CGP 41251 i n clinical trials.